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Molecular mechanisms and clinical phenotype of T3 receptor alpha mutations

Projectomschrijving

Werking receptor

Schildklierhormoon is essentieel voor een normale ontwikkeling. De werking van schildklierhormoon vindt plaats door binding aan een schildklierhormoonreceptor. Recent hebben wij en onderzoekers uit Engeland een nieuw ziektebeeld ontdekt, waarbij deze receptor niet goed functioneert. Het gevolg is dat schildklierhormoon zijn normale werking niet kan uitoefenen. Dit uit zich bij deze patiënten onder andere in een groeivertraging en ontwikkelingsachterstand.

Identificatie van nieuwe patiënten

Dit onderzoek richt zich op de identificatie van nieuwe patiënten en de ontrafeling van de moleculaire mechanismen die tot dit ziektebeeld leiden. Ons onderzoek is relevant omdat patiënten met dit nieuwe ziektebeeld waarschijnlijk goed behandeld kunnen worden met reeds beschikbare schildklierhormoontabletten.

Producten

Titel: Normal Thyroid Function and the Risk of Atrial Fibrillation: the Rotterdam Study
Auteur: Chaker, Layal, Heeringa, Jan, Dehghan, Abbas, Medici, Marco, Visser, W. Edward, Baumgartner, Christine, Hofman, Albert, Rodondi, Nicolas, Peeters, Robin P., Franco, Oscar H.
Magazine: Journal of Clinical Endocrinology & Metabolism
Titel: Thyroid Function Within the Reference Range and the Risk of Stroke: An Individual Participant Data Analysis
Auteur: Chaker, Layal, Baumgartner, Christine, den Elzen, Wendy P. J., Collet, Tinh-Hai, Ikram, M. Arfan, Blum, Manuel R., Dehghan, Abbas, Drechsler, Christiane, Luben, Robert N., Portegies, Marileen L. P., Iervasi, Giorgio, Medici, Marco, Stott, David J., Dullaart, Robin P., Ford, Ian, Bremner, Alexandra, Newman, Anne B., Wanner, Christoph, Sgarbi, José A., Dörr, Marcus, Longstreth, W. T., Psaty, Bruce M., Ferrucci, Luigi, Maciel, Rui M. B., Westendorp, Rudi G., Jukema, J. Wouter, Ceresini, Graziano,
Magazine: Journal of Clinical Endocrinology & Metabolism
Titel: Role of the Bile Acid Transporter SLC10A1 in Liver Targeting of the Lipid-Lowering Thyroid Hormone Analog Eprotirome
Auteur: Kersseboom, Simone, van Gucht, Anja L. M, van Mullem, Alies, Brigante, Giulia, Farina, Stefania, Carlsson, Bo, Donkers, Joanne M, van de Graaf, Stan F. J, Peeters, Robin P, Visser, Theo J
Magazine: Endocrinology
Titel: Diverse Genotypes and Phenotypes of Three Novel Thyroid Hormone Receptor-a Mutations
Auteur: Demir, Korcan, van Gucht, Anja L. M., Büyükinan, Muammer, Çatli, Gönül, Ayhan, Yavuz, Nijat Bas, Veysel, Dündar, Bumin, Özkan, Behzat, Meima, Marcel E., Visser, W. Edward, Peeters, Robin P., Visser, Theo J.
Magazine: Journal of Clinical Endocrinology & Metabolism
Titel: Resistance to Thyroid Hormone Alpha in an 18-Month-Old Girl: Clinical, Therapeutic, and Molecular Characteristics
Auteur: van Gucht, Anja L.M., Meima, Marcel E., Zwaveling-Soonawala, Nitash, Visser, W. Edward, Fliers, Eric, Wennink, Johanna M.B., Henny, Civile, Visser, Theo J., Peeters, Robin P., van Trotsenburg, A.S. Paul
Magazine: Thyroid
Titel: Eur J Epidemiol.
Titel: J Clin Endocrinol Metab.
Titel: Biochim Biophys Acta.
Titel: J Clin Endocrinol Metab.
Titel: Endocr Rev.
Titel: Age-dependent association of thyroid function with brain morphology and microstructural organization: evidence from brain imaging
Auteur: Chaker, Layal, Cremers, Lotte G.M., Korevaar, Tim I.M., de Groot, Marius, Dehghan, Abbas, Franco, Oscar H., Niessen, Wiro J., Ikram, M. Arfan, Peeters, Robin P., Vernooij, Meike W.
Magazine: Neurobiology of Aging
Titel: J Clin Endocrinol Metab.
Titel: Anemia in Patients With Resistance to Thyroid Hormone a: A Role for Thyroid Hormone Receptor a in Human Erythropoiesis
Auteur: van Gucht, Anja L M, Meima, Marcel E, Moran, Carla, Agostini, Maura, Tylki-Szymanska, Anna, Krajewska, Malgorzata-Walasek, Chrzanowska, Krystyna, Efthymiadou, Alexandra, Chrysis, Dionisios, Demir, Korcan, Visser, W Edward, Visser, Theo J, Chatterjee, Krishna, van Dijk, Thamar B, Peeters, Robin P
Magazine: Journal of Clinical Endocrinology & Metabolism
Titel: Clin Endocrinol (Oxf).
Titel: Eur Thyroid J.
Titel: J Clin Endocrinol Metab.
Titel: Thyroid function and the risk of dementia
Auteur: Chaker, Layal, Wolters, Frank J., Bos, Daniel, Korevaar, Tim I.M., Hofman, Albert, van der Lugt, Aad, Koudstaal, Peter J., Franco, Oscar H., Dehghan, Abbas, Vernooij, Meike W., Peeters, Robin P., Ikram, M. Arfan
Magazine: Neurology
Titel: Thyroid Function and Sudden Cardiac DeathClinical Perspective
Auteur: Chaker, Layal, van den Berg, Marten E., Niemeijer, Maartje N., Franco, Oscar H., Dehghan, Abbas, Hofman, Albert, Rijnbeek, Peter R., Deckers, Jaap W., Eijgelsheim, Mark, Stricker, Bruno H.C., Peeters, Robin P.
Magazine: Circulation
Titel: Resistance to Thyroid Hormone due to Heterozygous Mutations in Thyroid Hormone Receptor Alpha
Auteur: van Gucht, Anja L.M., Moran, Carla, Meima, Marcel E., Visser, W. Edward, Chatterjee, Krishna, Visser, Theo J., Peeters, Robin P.
Magazine: current topics in developmental biology
Titel: BMC Med.
Titel: Effects of thyroid hormone transporters MCT8 and MCT10 on nuclear activity of T3
Auteur: van Mullem, Alies A., van Gucht, Anja L.M., Visser, W. Edward, Meima, Marcel E., Peeters, Robin P., Visser, Theo J.
Magazine: Molecular and Cellular Endocrinology

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Samenvatting van de aanvraag

Thyroid hormone (TH) is essential for normal development and function of all tissues. The genomic action of TH is largely mediated by binding of the bioactive T3 to its nuclear receptor (TR). Two genes, THRA and THRB, encode TRs, with TRa1, TRb1 and TRb2 as the T3 binding isoforms. It has been known for more than twenty years that heterozygous mutations in the ligand-binding domain of THRB, that impair hormone binding and/or transcriptional activity of TRb1 and TRb2, result in resistance to TH (RTH). RTH is a well-documented syndrome characterized by elevated serum TH levels and a non-suppressed TSH, and a variable phenotype including goiter, tachycardia, and raised energy expenditure. We ourselves have identified 14 different THRB mutations in 20 unrelated RTH patients. Ever since its characterization in 1987, investigators have searched for patients with mutations in THRA without success until recently when we and others identified the first patients with inactivating mutations in TRa1. These patients show marked growth retardation, delayed bone development, and mildly delayed motor and mental development. Furthermore, they have growth hormone deficiency and altered thyroid function tests, mimicking biochemical alterations observed in patients with combined pituitary hormone deficiency. The different clinical phenotype of patients with inactivating mutations in THRA and THRB cannot be explained only by the different expression patterns of the receptors. Isoform-specific and tissue-specific effects of the different receptors may very well contribute to the differences in the clinical phenotype. The current project aims to unravel the molecular mechanisms leading to the clinical phenotype of patients with mutations in TRa1. The overall approach includes 1) the identification of new patients with mutations in THRA, 2) the analysis of the molecular mechanisms involved in the differential effects mediated by TRa1 and TRb1, and 3) the establishment of a genotype-phenotype correlation for this newly discovered clinical phenotype, using an integrative approach with various techniques such as exome sequencing, ChIP-Seq, expression profiling, and mass-spectrometry. These different strategies will improve our understanding of the role of TRa1 in health and disease. By combining clinical data obtained from patients with mutations in THRA with animal data and in vitro data from transfected cells, we will provide detailed new insights into the molecular mechanisms underlying the specific phenotype associated with these mutations. Furthermore, identification of additional patients with mutations in THRA is even more important because the available evidence suggests that these patients will benefit from treatment with TH.

Onderwerpen

Kenmerken

Projectnummer:
91212044
Looptijd: 100%
Looptijd: 100 %
2013
2017
Onderdeel van programma:
Gerelateerde subsidieronde:
Projectleider en penvoerder:
Prof. dr. R.P. Peeters
Verantwoordelijke organisatie:
Erasmus MC